High-dose palifermin administration promotes epithelial (eg, intestinal epithelial stem cells [IESCs]) protection by enhancing tissue repair and maintaining epithelial integrity. This protective effect reduces the exposure of damage-associated molecular patterns (DAMPs), which in turn favors immune regulation and reduces the risk of aGVHD. Palifermin’s ability to preserve epithelial integrity without directly modulating T-cell immunity highlights its potential as a novel approach for GVHD prophylaxis.